PROBUCOL INHIBITS NOT ONLY THE PROGRESSION OF ATHEROSCLEROTIC DISEASE, BUT CAUSES A DIFFERENT COMPOSITION OF ATHEROSCLEROTIC LESIONS IN WHHL-RABBITS

Watanabe heritable hyperlipidaemic (WHHL)rabbits develop premature ath erosclerosis due to an inborn defect of the low-density lipoprotein (L DL) receptor causing severe hypercholesterolaemia. Probucol, which pos sesses a lipid lowering and an antioxidative potency, has been shown t o reduce the extent of atherosclerotic disease in this animal. The obj ect of the present study was the detailed analysis of the cellular and non-cellular composition of atherosclerosic lesions in WHHL-rabbits t reated with probucol when compared with untreated controls. In two ind ependent sets of experiments, each consisting of one litter, a total n umber of 5 animals was fed a diet containing 1% (w/w) probucol. Four a nimals served as controls and 2 animals were sacrificed before treatme nt (at 2 and 4 months of age, respectively) to define the baseline lev el of the atherosclerotic disease. Morphemetric analysis was employed in order to determine plaque area macroscopically by planimetry and pl aque thickness and composition histologically, in 30 cross-sections of the aorta of each animal. In the group treated with probucol, a dimin ution of plaque area and thickness, as well as a decrease of foam cell and - especially in one experiment necrotic content of atheroscleroti c lesions, was observed. Plaques from aortas of animals treated with p robucol consisted predominantly of smooth muscle cells and compact int ercellular fibrous structures. Furthermore, as an additional character istic feature of the ''typical'' probucol plaque, they usually lacked confluent necrotic cores. In comparison with untreated animals, there was also a decrease in intracellular apolipoprotein B (ape B) as deter mined by immunohistochemistry. These data confirm the antiatherosclero tic potency of probucol in the WHHL-rabbit. Moreover, it was demonstra ted that there is a different type of atherosclerosis present in the g roup treated with probucol. The mechanism behind these shifts may be b ased on the antioxidative property as well as on direct effects of pro bucol on cellular plaque components.